PROJECT SUMMARY/ABSTRACT Drinking water contaminated by per- and polyfluoroalkyl substances (PFAS) has affected millions worldwide, including Michiganders at over 50 confirmed sites and 64 public water supplies. PFAS exposure has been linked to altered immune, endocrine, and liver function and to abnormal reproduction and development and possibly carcinogenesis. The Agency for Toxic Substances and Disease Registry (ATSDR) multi-site health study is an important step toward the long-term goal of characterizing the toxicity of PFAS along these endpoints, and including Michigan markedly strengthens this national study. Michigan?s cohort will enable ATSDR to capture a range of documented exposures to PFAS in areas where (1) we have a clear understanding of the source and extent of the exposure, essential to reconstructing historical levels of water contamination; (2) the geographic scope of water contamination has been delineated; and (3) communities are supportive of engaging in activities to better understand the impact of these exposures on their individual and collective health. We will securely and effectively conduct data analysis and historical reconstruction, including water modeling, physiologically based pharmacokinetic (PBPK) modeling where appropriate, and statistical analysis of the relationship between chemical exposure and health outcomes. The Michigan Department of Health and Human Services (MDHHS) and its Investigative Team will leverage existing public health infrastructure, including well-established relationships with the proposed communities, and ongoing PFAS exposure assessments and environmental investigations across the state to effectively and efficiently complete the core research protocol. We will expand on the core research by using newborn blood spot data to understand (1) historical and current infant PFAS blood levels and (2) relationships between newborn PFAS blood level and pregnancy complications (e.g., preeclampsia) and infant health effects (e.g., birth weight, thyroid function). This proposal represents a target sample population of 2,000 adults (male and female) and 600 children ages 4 to 17 years old allocated evenly among municipal and residential well users at two sites. As stated in the core protocol, we will collect data from adults and children who have been exposed to PFAS-contaminated water any time since 2005. Participants will attend a local clinic during which they will complete questionnaires, have anthropometric measurements taken, and provide blood and urine samples. Consent for medical records abstraction will also be requested. Children will complete several neurobehavioral assessments, and school records will be sought for analysis. The core protocol will be followed exactly. In the investigator-initiated research, our investigative team will request consent for newborn blood spot testing. We are positioned to fully involve these proposed communities and to implement future public health responses and clinical guidance in light of the Michigan and nationwide study results collected as part of this initiative. Not only will the proposed research advance scientific understanding of PFAS toxicity, but it will also inform local, state, and national public health response to these contaminants.